The DOI matches its Crossref record; 48 of the 50 references it cites were found in a registry or an index, and 2 are not checked yet.
Multifunctional oncolytic nanoparticles deliver self-replicating IL-12 RNA to eliminate established tumors and prime systemic immunity
Open accessAbstract
Therapies that synergistically stimulate immunogenic cancer cell death (ICD), inflammation, and immune priming are of great interest for cancer immunotherapy. However, even multi-agent therapies often fail to trigger all of the steps necessary for self-sustaining anti-tumor immunity. Here we describe self-replicating RNAs encapsulated in lipid nanoparticles (LNP-replicons), which combine three key elements: (1) an LNP composition that potently promotes ICD, (2) RNA that stimulates danger sensors in transfected cells, and (3) RNA-encoded IL-12 for modulation of immune cells. Intratumoral administration of LNP-replicons led to high-level expression of IL-12, stimulation of a type I interferon response, and cancer cell ICD, resulting in a highly inflamed tumor microenvironment and priming of systemic anti-tumor immunity. In several mouse models of cancer, a single intratumoral injection of replicon-LNPs eradicated large established tumors, induced protective immune memory, and enabled regression of distal uninjected tumors. LNP-replicons are thus a promising multifunctional single-agent immunotherapeutic.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Alternatively to vaccination, a pro-inflammatory tumour microenvironment can be induced by lipid nanoparticle–mRNA formulations delivering cytokines or co-stimulatory molecules33,106,161,163,214 (Table 2).”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [106]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Cluster analysis and display of genome-wide expression patterns
Eisen, M. B., Spellman, P. T., Brown, P. O., & Botstein, D. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.25.14863 · Cited by 16,184
Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma
Wolchok, J. D., Chiarion-Sileni, V., Gonzalez, R., Rutkowski, P., Grob, J.-J., Cowey, C. L., Lao, C. D., Wagstaff, J., Schadendorf, D., Ferrucci, P. F., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1709684 · Cited by 5,357
Elements of cancer immunity and the cancer–immune set point
Chen, D. S., & Mellman, I. (2017) · Nature · doi:10.1038/nature21349 · Cited by 5,352
The future of immune checkpoint therapy
Sharma, P., & Allison, J. P. (2015) · Science · doi:10.1126/science.aaa8172 · Cited by 4,878
Release of chromatin protein HMGB1 by necrotic cells triggers inflammation
Scaffidi, P., Misteli, T., & Bianchi, M. E. (2002) · Nature · doi:10.1038/nature00858 · Cited by 4,221
Calreticulin exposure dictates the immunogenicity of cancer cell death
Obeid, M., Tesniere, A., Ghiringhelli, F., Fimia, G. M., Apetoh, L., Perfettini, J.-L., Castedo, M., Mignot, G., Panaretakis, T., Casares, N., et al. (2007) · Nature Medicine · doi:10.1038/nm1523 · Cited by 3,216
Immunogenic cell death in cancer and infectious disease
Galluzzi, L., Buqué, A., Kepp, O., Zitvogel, L., & Kroemer, G. (2017) · Nature Reviews Immunology · doi:10.1038/nri.2016.107 · Cited by 3,119
Apetoh, L., Ghiringhelli, F., Tesniere, A., Obeid, M., Ortiz, C., Criollo, A., Mignot, G., Maiuri, M. C., Ullrich, E., Saulnier, P., et al. (2007) · Nature Medicine · doi:10.1038/nm1622 · Cited by 3,056
Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma
Andtbacka, R. H. I., Kaufman, H. L., Collichio, F. A., AMATRUDA, T. T., Senzer, N. N., Chesney, J. A., Delman, K. A., S̄pitler, L. E., Puzanov, I. J., Agarwala, S. S., et al. (2015) · Journal of Clinical Oncology · doi:10.1200/jco.2014.58.3377 · Cited by 2,728
Zou, W., Wolchok, J. D., & Chen, L. (2016) · Science Translational Medicine · doi:10.1126/scitranslmed.aad7118 · Cited by 2,400
Ghiringhelli, F., Apetoh, L., Tesniere, A., Aymeric, L., Ma, Y., Ortiz, C., Vermaelen, K., Panaretakis, T., Mignot, G., Ullrich, E., et al. (2009) · Nature Medicine · doi:10.1038/nm.2028 · Cited by 1,898
Kawai, T., & Akira, S. (2006) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4401850 · Cited by 1,894
Oncolytic viruses: a new class of immunotherapy drugs
Kaufman, H. L., Kohlhapp, F. J., & Zloza, A. (2015) · Nature Reviews Drug Discovery · doi:10.1038/nrd4663 · Cited by 1,724
Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti-PD-1 immunotherapy
Ribas, A., Dummer, R., Puzanov, I., VanderWalde, A., Andtbacka, R. H. I., Michielin, O., Olszanski, A. J., Malvehy, J., Cebon, J., Fernandez, E., et al. (2017) · Cell · doi:10.1016/j.cell.2017.08.027 · Cited by 1,520
Cancer cell–autonomous contribution of type I interferon signaling to the efficacy of chemotherapy
Sistigu, A., Yamazaki, T., Vacchelli, E., Chaba, K., Enot, D. P., Adam, J., Vitale, I., Goubar, A., Baracco, E. E., Remédios, C., et al. (2014) · Nature Medicine · doi:10.1038/nm.3708 · Cited by 1,042
TSLP Elicits IL-33–Independent Innate Lymphoid Cell Responses to Promote Skin Inflammation
Kim, B., Siracusa, M. C., Saenz, S. A., Noti, M., Monticelli, L. A., Sonnenberg, G. F., Hepworth, M. R., Voorhees, A. S. V., Comeau, M. R., & Artis, D. (2013) · Science Translational Medicine · doi:10.1126/scitranslmed.3005374 · Cited by 735
Phase I trial of interleukin-12 plasmid electroporation in patients with metastatic melanoma
Daud, A. I., DeConti, R. C., Andrews, S., Urbas, P., Riker, A. I., Sondak, V. K., Munster, P. N., Sullivan, D. M., Ugen, K. E., Messina, J. L., et al. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2007.15.6794 · Cited by 701
Necrotic cells trigger a sterile inflammatory response through the Nlrp3 inflammasome
Iyer, S. S., Pulskens, W. P., Sadler, J. J., Butter, L. M., Teske, G. J., Ulland, T. K., Eisenbarth, S. C., Florquin, S., Flavell, R. A., Leemans, J. C., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0908698106 · Cited by 691
Moynihan, K. D., Opel, C. F., Szeto, G. L., Tzeng, A., Zhu, E. F., Engreitz, J., Williams, R. T., Rakhra, K., Zhang, M. H., Rothschilds, A. M., et al. (2016) · Nature Medicine · doi:10.1038/nm.4200 · Cited by 528
Self-citationInterleukin 12: still a promising candidate for tumor immunotherapy?
Lasek, W., Zagożdżon, R., & Jakobisiak, M. (2014) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-014-1523-1 · Cited by 495
Systemic clinical tumor regressions and potentiation of PD1 blockade with in situ vaccination
Hammerich, L., Marron, T. U., Upadhyay, R., Svensson‐Arvelund, J., Dhainaut, M., Hussein, S., Zhan, Y., Ostrowski, D., Yellin, M. J., Marsh, H. C., et al. (2019) · Nature Medicine · doi:10.1038/s41591-019-0410-x · Cited by 448
Oncolytic viruses as engineering platforms for combination immunotherapy
Twumasi‐Boateng, K., Pettigrew, J. L., Kwok, Y. Y. E., Bell, J. C., & Nelson, B. H. (2018) · Nature reviews. Cancer · doi:10.1038/s41568-018-0009-4 · Cited by 430
Durable anticancer immunity from intratumoral administration of IL-23, IL-36γ, and OX40L mRNAs
Hewitt, S. L., Bai, A., Bailey, D., Ichikawa, K., Zielinski, J., Karp, R., Apte, A., Arnold, K., Zacharek, S. J., Iliou, M. S., et al. (2019) · Science Translational Medicine · doi:10.1126/scitranslmed.aat9143 · Cited by 316
Chiocca, E. A., Yu, J. S., Lukas, R. V., Solomon, I. H., Ligon, K. L., Nakashima, H., Triggs, D., Reardon, D. A., Wen, P. Y., Stopa, B. M., et al. (2019) · Science Translational Medicine · doi:10.1126/scitranslmed.aaw5680 · Cited by 264
An Orthogonal Array Optimization of Lipid-like Nanoparticles for mRNA Delivery in Vivo
Li, B., Luo, X., Deng, B., Wang, J., McComb, D. W., Shi, Y., Gaensler, K. M. L., Tan, X., Dunn, A. L., Kerlin, B. A., et al. (2015) · Nano Letters · doi:10.1021/acs.nanolett.5b03528 · Cited by 261
Self-citationNanotoxicity: A Key Obstacle to Clinical Translation of siRNA-Based Nanomedicine
Xue, H. Y., Liu, S., & Wong, H. L. (2014) · Nanomedicine · doi:10.2217/nnm.13.204 · Cited by 259
Lucas, M. L., Heller, L. C., Coppola, D., & Heller, R. F. (2002) · Molecular Therapy · doi:10.1006/mthe.2002.0601 · Cited by 253
Intratumoral Delivery of Immunotherapy—Act Locally, Think Globally
Aznar, M. A., Tinari, N., Rullan, A., Sánchez-Paulete, A. R., Rodriguez-Ruiz, M. E., & Melero, I. (2016) · The Journal of Immunology · doi:10.4049/jimmunol.1601145 · Cited by 229
Intratumoral Immunization: A New Paradigm for Cancer Therapy
Marabelle, A., Kohrt, H. E. K., Caux, C., & Levy, R. (2014) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-13-2116 · Cited by 221
Momin, N., Mehta, N. K., Bennett, N. R., Ma, L., Palmeri, J. R., Chinn, M. M., Lutz, E. A., Kang, B. H., Irvine, D. J., Spranger, S., et al. (2019) · Science Translational Medicine · doi:10.1126/scitranslmed.aaw2614 · Cited by 206
Self-citationWang, J., Perry, C. J., Meeth, K., Thakral, D., Damsky, W., Micevic, G., Kaech, S., Blenman, K., & Bosenberg, M. (2017) · Pigment Cell & Melanoma Research · doi:10.1111/pcmr.12591 · Cited by 199
Extrinsic Phagocyte-Dependent STING Signaling Dictates the Immunogenicity of Dying Cells
Ahn, J., Xia, T., Rabasa, A., Betancourt, D. M., & Barber, G. N. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.03.027 · Cited by 194
McComb, S., Cessford, E., Alturki, N. A., Joseph, J., Shutinoski, B., Startek, J. B., Gamero, A. M., Mossman, K. L., & Sad, S. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1407068111 · Cited by 190
In situ vaccination: Cancer immunotherapy both personalized and off‐the‐shelf
Hammerich, L., Binder, A. F., & Brody, J. (2015) · Molecular Oncology · doi:10.1016/j.molonc.2015.10.016 · Cited by 188
Wang, P., Li, X., Wang, J., Gao, D., Li, Y., Li, H., Chu, Y., Zhang, Z., Liu, H., Jiang, G., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-01385-8 · Cited by 175
Self-citationQuetglas, J. I., Labiano, S., Aznar, M. A., Bolaños, E., Azpilikueta, A., Rodríguez, I., Casales, E., Sánchez-Paulete, A. R., Segura, V., Smerdou, C., et al. (2015) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-14-0216 · Cited by 115
Kim, M. K., Breitbach, C. J., Moon, A., Heo, J., Lee, Y. K., Cho, M., Lee, J. W., Kim, S.-G., Kang, D. H., Bell, J. C., et al. (2013) · Science Translational Medicine · doi:10.1126/scitranslmed.3005361 · Cited by 101
Barrett, J. A., Cai, H., Miao, J., Khare, P. D., Gonzalez, P., Dalsing-Hernandez, J. E., Sharma, G., Chan, T., Cooper, L. J. N., & Lebel, F. M. (2018) · Cancer Gene Therapy · doi:10.1038/s41417-018-0019-0 · Cited by 101
Lipid Nanoparticles for Delivery of Therapeutic RNA Oligonucleotides
Moss, K. H., Popova, P. G., Hadrup, S. R., Astakhova, K., & Taskova, M. (2019) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.8b01290 · Cited by 101
Bhatia, S., Longino, N. V., Miller, N. J., Kulikauskas, R. M., Iyer, J. G., Ibrani, D., Blom, A., Byrd, D. R., Parvathaneni, U., Twitty, C., et al. (2019) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-0972 · Cited by 95
In vitro evolution of enhanced RNA replicons for immunotherapy
Li, Y., Teague, B., Zhang, Y., Su, Z., Porter, E., Dobosh, B., Wagner, T., Irvine, D. J., & Weiss, R. (2019) · Scientific Reports · doi:10.1038/s41598-019-43422-0 · Cited by 71
Self-citationCharacterization of abscopal effects of intratumoral electroporation-mediated IL-12 gene therapy
Mukhopadhyay, A., Wright, J. H., Shirley, S. A., Canton, D. A., Burkart, C., Connolly, R. J., Campbell, J. S., & Pierce, R. H. (2018) · Gene Therapy · doi:10.1038/s41434-018-0044-5 · Cited by 52
van Herpen, C. M., Huijbens, R. J. F., Looman, M. W. G., de Vries, I. J. M., Marres, H. A. M., Ven, J. V. D., Hermsen, R. C., Adema, G. J., & de Mulder, P. H. (2003) · PubMed · Cited by 49
Rodríguez-Madoz, J. R., Liu, K. H., Quetglas, J. I., Ruiz-Guillen, M., Otano, I., Crettaz, J. S., Butler, S. D., Bellezza, C. A., Dykes, N. L., Tennant, B. C., et al. (2009) · Journal of Virology · doi:10.1128/jvi.01597-09 · Cited by 45
Selzner, N., Selzner, M., Graf, R., Ungethuem, U., Fitz, J., & Clavien, P. (2004) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4401505 · Cited by 42
Li, Y., Shen, C., Zhu, B., Shi, F., Eisen, H. N., & Chen, J. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1500451 · Cited by 17
Self-citationBrenneman, G. (2012) · SpringerReference · doi:10.1007/springerreference_223678 · Cited by 4
Morphology of DOTAP and TT3 lipid nanoparticles with or without self-replicating RNA
Li, Y., Irvine, D. J., & Weiss, R. (2020) · Figshare · doi:10.6084/m9.figshare.12498047
Self-citationLi, Y., Irvine, D. J., & Weiss, R. (2020) · Figshare · doi:10.6084/m9.figshare.12502007
Self-citationLi, Y., Irvine, D. J., & Weiss, R. (2020) · Figshare · doi:10.6084/m9.figshare.12502124
Self-citation
Research works printed but not linked: 1
- Van Herpen, C. M. et al. Pharmacokinetics and immunological aspects of a phase Ib study with intratumoral administration of recombinant human interleukin-12 in patients with head and neck squamous cell carcinoma. Clin. Cancer Res. 9, 2950–2956 (2003).
Cited by
Sorted by citations
Lipid nanoparticles for mRNA delivery
Hou, X., Zaks, T., Langer, R., & Dong, Y. (2021) · Nature Reviews Materials · doi:10.1038/s41578-021-00358-0 · Cited by 4,076
Self-citationInterleukins in cancer: from biology to therapy
Briukhovetska, D., Dörr, J., Endres, S., Libby, P., Dinarello, C. A., & Kobold, S. (2021) · Nature reviews. Cancer · doi:10.1038/s41568-021-00363-z · Cited by 822
Intratumoural administration and tumour tissue targeting of cancer immunotherapies
Melero, I., Álvarez, E. C., Álvarez, M., Champiat, S., & Marabelle, A. (2021) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-021-00507-y · Cited by 505
mRNA-based cancer therapeutics
Liu, C., Shi, Q., Huang, X., Koo, S., Kong, N., & Tao, W. (2023) · Nature Reviews Cancer · doi:10.1038/s41568-023-00586-2 · Cited by 500
Chen, J., Ye, Z., Huang, C., Qiu, M., Song, D., Li, Y., & Xu, Q. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2207841119 · Cited by 425
Self-citation
Metadata
- Authors
- Li, Y., Su, Z., Zhao, W., Zhang, X., Momin, N., Zhang, C., Wittrup, K. D., Dong, Y., Irvine, D. J., & Weiss, R.
- Affiliations
- Koch Institute for Integrative Cancer Research At MIT (US)
- The Ohio State University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Dong, Yizhou
- Irvine, Darrell J.
- Weiss, Ron
- ORCID
- Venue
- Nature Cancer
- Published
- 2020-08-10
- Volume
- 1
- Issue
- 9
- Pages
- 882-893
- ISSN
- 2662-1347 (ISSN-L)
- PMC
- PMC8386348
- OpenAlex
- W3047822613
- Cited by
- 233
- References
- 47
- Citations by year
- 2026: 24 · 2025: 45 · 2024: 58 · 2023: 43 · 2022: 34 · 2021: 26 · 2020: 3
- FWCI
- 9.28
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Cancer (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | NCI | Division of Cancer Epidemiology and Genetics, National Cancer Institute (P30-CA14051, CA20618)
- Howard Hughes Medical Institute
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (CA20618)
- U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (R35GM119679)
- Professor Sylvan G. Frank Graduate Fellowship
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- self-replicating RNA, IL-12, immunogenic cancer cell death, cancer immunotherapy, type I interferon response, tumor microenvironment inflammation, systemic antitumor immunity, immunological memory, intratumoral injection
- MeSH terms
- Animals, Immunotherapy, Liposomes, Neoplasms, RNA, Interleukin-12, Mice, Nanoparticles, Tumor Microenvironment
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
